DESCRIPTION (Applicant's Description): Candidate: Ralph Scully's career goal is to achieve full independence as a clinician scientist dedicated to research having an impact upon human breast cancer. His postdoctoral years in Dr. David Livingston's laboratory were spent studying the function of the hereditary breast- ovarian tumor suppressor gene product, BRCA1. His objective in seeking support in the form of a Howard Temin Award is to make the transition to full independence as an unmentored scientist, while continuing to develop an understanding of molecular genetics, coupling biochemical and molecular biology skills in the further study of BRCA1 function. Environment: The Dana-Farber Cancer Institute provides an outstanding collaborative environment for the completion of this period of mentored research. In particular, Dr. David Livingston's skills in mentoring the development of clinician scientists is widely recognized. Research: The specific research aims are: 1. to use currently available cell lines lacking wild-type BRCA1 as a means of investigating BRCA1 function. The focus will be upon the concept, suggested by the BRCA1-Rad51 interaction, that BRCA1 plays a role in maintaining genome integrity. Two cell functions connected with genome integrity maintenance will be explored: DNA repair and DNA damage-dependent cell cycle checkpoint function. 2. to define in detail the sites of BRCA1 targeted for phosphorylation after DNA damage. A collaboration with Dr. Inder Verma's laboratory (Salk Institute) will facilitate the identification of sites on BRCA1 specifically phosphorylated after DNA damage. This work will lead to attempts to assay for the functional meaning of these phosphorylation events, and to attempt to identify upstream components of the signaling cascade linking DNA damage to BRCA1 phosphorylation. 3. to determine whether phosphorylation of BRCA1 regulates its interaction with other cellular proteins. A number of approaches are outlined aimed at identifying/cloning BRCA1-associated proteins based upon knowledge of BRCA1 phosphorylation target sites.